Patients with serious disease who are potential research subjects are routinely described as "vulnerable"and as disproportionately anticipating direct benefit from participation in early-phase trials. In our 1999-2003 ELSI project, "The Social Construction of Benefit in Gene Transfer Research", we explored how benefit in gene transfer research (GTR) is discussed and understood, and whether and how the "therapeutic misconception" exists in GTR. Our data identified individual, institutional, social, and structural factors associated with vulnerability and the therapeutic misconception in GTR, but we also found that the relationship between expectation of direct benefit for subjects and these factors is complex and may call into question some generally held assumptions. This competing continuation project therefore proposes to use our exceptionally rich qualitative and quantitative data in a deeper conceptual and analytical investigation of benefit in GTR, with three linked but independent components: 1) development of a multifactorial model of influence in GTR, to replace the static and problematic notion of vulnerability, based on research relationships, analyzing research participation as a form of social exchange, and delineating a dynamic continuum of influences, ranging from 'due' to 'undue', affecting all parties to research relationships; 2) development of a benefit threshold for assessing what may be offered as a "reasonable prospect of direct benefit" for subjects in early-phase GTR, including how study endpoints relate to direct benefit, specificity in discussion of direct benefit in early-phase research, the effects of trial design features on direct benefit, and assessment of collateral ("inclusion") and societal benefit; and 3) application of our influence model and benefit threshold to a close examination of the "vulnerable" population of children in GTR studies, where special regulatory guidance, the dual problems of inclusion and access, and growth and change in the field of GTR affect how benefit in pediatric GTR is viewed by IRBs, investigators, and families. Products of this research will be: 1) empirically and conceptually based analyses published in the scholarly literature, and 2) policy recommendations, guidance documents, and policy-relevant materials disseminated to research oversight bodies and policymakers, scientific and professional organizations for GTR and other research, and patient advocacy groups.